Azides with active methylene compounds

The base-catalyzed condensation of azides with activated methylene compounds is a well-established route to IJT-triazoles. In particular, it is the best route to triazoles bearing a 5-amino or hydroxy substituent and an aryl or carbonyl-containing function in the 4-position. The addition is regiospecific. The reaction is a stepwise one, since anomerism of glycosyl azides has been observed in their reaction with activated methylene compounds, indicating the presence of an intermediate. The mechanism can be envisaged as a nucleophilic attack by the car-banion on the terminal nitrogen of the azide, followed by cyclization to a... 

The reaction of azides with active methylene compounds is an especially attractive route to the acid derivatives. An early report involving aryliodo-azides (Eq. 34) showed excellent yields. llie methyltropolonyl azide (4.2-11) reacts smoothly with several active methylene substrates (Eq. 35), most of which give amino products that are to be discussed in Chapter X. Sodamide has also shown good results as a catalyst for these reactions (Eq. 36). ... 

The reaction of azides with active methylene compounds under basic conditions is the most widely used approach to the u-triazole amino adds (Eqs. 1,2)/" This reaction, discovered by Dimroth, is highly regiospedfic and produces good to excellent yields for a variety of substituents (Eq. 3)/... 

The diazo transfer reaction between p-toluenesulfonyl azide and active methylene compounds is a useful synthetic method for the preparation of a-diazo carbonyl compounds. However, the reaction of di-tert-butyl malonate and p-toluenesulfonyl azide to form di-tert-butyl diazomalonate proceeded to the extent of only 47% after 4 weeks with the usual procedure." The present procedure, which utilizes a two-phase medium and methyltri-n-octylammonium chloride (Aliquat 336) as phase-transfer catalyst, effects this same diazo transfer in 2 hours and has the additional advantage of avoiding the use of anhydrous solvents. This procedure has been employed for the preparation of diazoacetoacetates, diazoacetates, and diazomalonates (Table I). Ethyl and ten-butyl acetoacetate are converted to the corresponding a-diazoacetoacetates with saturated sodium carbonate as the aqueous phase. When aqueous sodium hydroxide is used with the acetoace-tates, the initially formed a-diazoacetoacetates undergo deacylation to the diazoacetates. Methyl esters are not suitable substrates, since they are too easily saponified under these conditions. 

Sulfonyl azides are exceptional in that they do not normally give triazoles with activated methylene compounds nucleophilic attack by the carbanion is usually followed by loss of the sulfonamide anion, giving a diazo compound as the product. Possible mechanisms for the reaction are illustrated (Scheme 8) for diethyl malonate. Attack of the carbanion on the terminus of the azide gives the anion of the linear triazene (1). 

Azide addition to enolizable ketones is regiospecific and may be considered as a 1,3-dipolar cycloaddition occurring at the double bond of the enolate, similar to the addition of azides to electron-rich olefins. However, a stepwise reaction appears more probable because glycosyl azides exhibit anomerism when they react with activated methylene compounds, thus indicating the presence of a triazene intermediate.264 On the other hand, the formation of the triazene intermediate may be considered as a limited case of 1,3-dipolar cycloaddition where one of the bonds is formed completely before the other one starts,2 such a limited case being observed for the Diels-Alder reaction.265... 

When treated with active methylene compounds e.g. malononitrile, in K2COi/DMSO systems the azides (106) cyclise to form the imidazotetrazoles (107) which may be isolated as their alkali metal salts <95JHC457>. On treatment with acid these salts are transformed into imidazoyl triazoles (Scheme 15). 

The possible mechanism for diazo transfer from p-toluenesulfonyl azide to active methylene compound 3 (flanked by carbonyl groups) is depicted below.1,3 Deprotonation of a-keto ester 3 with NEt3 leads to enolate 4 which attacks at the electrophilic N of the sulfonyl azide 5 to give intermediate tosyl derivative 6. Proton transfer occurs within intermediate 6 followed by elimination of p-toluenesulfonamide, leading to diazo compound 7 and the by-product -toluene sulfonamide 8.1,3... 

As reported in 1902, the substrate scope of the Dimroth triazole synthesis was limited to aromatic azides. An early extension of this methodology was reported in 1956 by Hoover and Day at the University of Pennsylvania. IH-1,2,3-Triazoles were of particular interest at the time as potential modifiers of nucleic acid metabolism. As part of a program directed at cancer chemotherapies, they replaced the azide aromatic moiety with a benzyl substituent. Sodium ethoxide-promoted reaction of benzyl azide (19) with active methylene compounds 25 provided 1-benzyl-1,2,3-triazoles 26 that could undergo reductive cleavage with sodium in liquid ammonia to afford the desired 4,5-disubstituted species. While various active methylene compounds were successfully used (ethyl cyanoacetate, cyanoacetamide, cyanoacetic acid, and malononitrile), the yields were low to modest when compared with aromatic substrates. ... 

Just like the aryl azides 2, the vinyl azides 11 are more reactive in their cycloadditions with active methylene compounds than are alkyl azides. In 1970, Alfred Hassner et al. developed a general synthetic approach to 1-vinyl-1,2,3-triazoles 12 and 14, (Scheme 4.4) [6] by the cycloaddition of active methylene compounds 10 or 13 with vinyl azides 11 (or their precursors, the P-haloalkyl azides), in the presence of 1 equiv. of an alkoxide (NaOMe). Decarboxylation of the l- dnyl-5-substituted l,2,3-triazole-4-carboxylic acids 14 synthesized from the reaction of ethyl acetoacetate or ethyl benzoylacetate with vinyl and P-haloalkyl azides led to 1-vinyl-5-substituted 1,2,3-triazoles in almost quantitative yield [6]. 

In 1991, Wright et al. reported a procedure for the preparation of substituted 1-benzyl-1//-1,2,3-triazoles 21 and 23 from benzyl azides 20 under very mild conditions (Scheme 4.7) [9]. Benzyl azides 20 reacted with active methylene compounds in DMSO induced by potassium carbonate at 35-40 C to give 1-benzyl-1//-1,2,3-triazoles 21 and 23 usually in good yield. Acetonitrile derivatives 10 gave 5-amino-l-benzyl-l//-l,2,3-triazoles 21, whereas diethyl malonate gave 5-hydroxy-l-benzyl-l//-l,2,3-triazoles. l//-l,2,3-Triazole-4-carboxylate esters and l//-l,2,3-triazole-4-ketones were obtained from ethyl acetoacetate and P-diketones, respectively. Benzyl methyl ketone reacted to give a 5-methyl-4-phenyl-l//-l,2,3-triazole, but acetone and acetophenone failed to react. Other active methylene compounds that did not react under these reaction conditions included ethyl cyanoacetate, ethyl fluoroacetate, and ethyl nitroacetate. 

Triazoles have also been obtained when the carbon atom adjacent to the activated methylene group carries a nitrogen function (i.e., amides, nitriles, amidines, and imines - ). In many of these cases it is impossible to decide, without N-labeling experiments, whether the third nitrogen of the triazole ring is derived from the toluene-p-sulfonyl azide or from the activated methylene compound. With amides, amidines, and nitriles, the first possibility seems more reasonable, but with imines, the third nitrogen is that of the imino group (Scheme... 

Diazo compounds have previously been prepared by a variety of methods. Some of these methods Include hydrazone oxidations, the reaction of diazomethane with acid chlorides,4 the reaction of activated methylene compounds with tosyl azide, decomposition of N-nitroso compounds, ... 

When active methylene compounds in basic medium react with tosyl azide, triazoles are never formed (Section IV,A,4), but the unstable triazoline intermediate undergoes a diazo transfer reaction in a Dimroth-type rearrangement.447 A typical example is the addition of tosyl azide to a 1,3-diketone... 

In aprotic medium (anhydrous acetone at reflux) triethylamine deprotonates 3-alkylben-zothiazolylium salts yielding an intermediate carbene (66) which can form a dimer (67 Scheme 37), or be trapped giving adducts with tetracyanoethylene (68), azides (69), or giving insertion derivatives with benzaldehyde (70) or activated methylene compounds (71). 

Diazo compounds couple with active methylene groups under basic conditions. Using one mole of the azide with two moles of methylene... 

Regitz, M. Reaction of active methylene compounds with azides. I. New synthesis of a-diazo-P-dicarbonyl compounds from... 

The first successful syntheses of phosphorus-containing diazoalkyl compounds (1) appear to have been reported independently by two groups of workers. Petzold and Henning employed a method presently described as that of diazo transfer, in which an active methylene compound, as its anion, is treated with an aromatic sulphonyl azide. Seyferth et al on the other hand, reported on a development to the Bamford-Stevens reaction, in which a carbonyl/7-toluenesulphonylhydrazone is treated with a base. Both methods thus depend on modifications to compounds with existing phosphorus-carbon bonds, as do other procedures which have since been developed. 

In this procedure, the C-phosphorylated active methylene compound is first converted into its anion, through its reaction with KOBu BuLi, PhLi, NaH or even Et3N, and the anion is then acted upon by a sulphonyl azide the latter has been / -toluenesulphonyl azide in most recorded examples of the reaction. The first example of the adoption of this procedure to the synthesis of a phosphonic acid derivative appears to have been the conversion of triethyl phosphonoacetate into the diazo derivative (2). Since then, the procedure has been used to obtain A-substituted derivatives of the phosphonoacetamide corresponding to structure 2, but the primary amide itself undergoes further reaction to afford the C-phosphorylated 1,2,3-triazole (3)". Tetraethyl methylenebisphosphonate yields tetraethyl... 

As mentioned already in Section 2.6, it is somewhat arbitrary to discuss diazo transfer reactions to alkenes in isolation from those to activated methylene compounds. The most important activation in methylene compounds is that of a neighboring carbonyl group and, as a consequence, the active methylene compound is in equilibrium with the corresponding enol, i.e., with an alkene as established by the systematic work of Huisgen (review Huisgen, 1984), typical diazo transfers involve 1,3-dipolar cycloaddition of a 1,3-dipole (azides) to a multiple-bond system, the dienophile (see Chapt. 6). In diazo transfer, this dienophile is an alkene or an alkyne, and the primary product is a A -l,2,3-triazoline or a A -l,2,3-triazole,... 

The diazo transfer reactions, discussed in the synthesis Sections 2.6-2.8 clearly indicate that arylsulfonyl azides and other compounds with the azido group act as electrophilic reagents, that add to nucleophiles, e.g., to C-anions of so-called active methylene compounds. This result is qualitatively easy to comprehend, since the N()8) and N(y)-atoms of the azides are electronically similar to the diazonio group, as shown in the mesomeric structures 4.20b-4.20c. 

L abbe and his collaborators have also demonstrated the importance of electronic effects in the synthesis of 1-vinyl-1,2,3-triazoles by adding azides ta either acetylenes (Eq. 15) or active methylene compounds (Eq. 16). In both cases iodoalkyl azides may be added, with comparable results, to produce precursors of 2.2-4 and 2.2-5. This very productive group has pioneered the excellent general method for l,5-disub tituted-l,2,3-triazoles involving phosphorus ylides (Eq. 17). The high yields and wide range of substituents employed makes this method most attractive. Product structures were demonstrated by the Dimroth addition and decarboxylation (Eq. 16). 

L abb6 and his collaborators have added azides to both active methylene compounds (Eq. if and acetylenes (Eq. 8) for the preparation of unusual examples of 1,2,3-triazoIes. With ethyl azidoformate (10.1-3) the initially formed 1-ester (10.1-4) rearranges on workup to the 2-substituted product... 

The venerable Dimroth triazole synthesis is a base-catalyzed condensation of an azide 1 with an active methylene compound 2 to provide a 1,2,3-triazole derivative 3. Commonly, this reaction is run with an alkoxide base in the corresponding alcohol solvent at ambient temperature or reflux/ "" ... 

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